Prostate cancer (PCa) remains the second leading cause of cancer death in men in the United States. The long term goal of this application is to develop an effective and safe strategy for prevention of PCa in men using a novel high (-tocopherol (T) rich mixture of tocopherols (?-TmT). Rationale for the studies proposed in this application is derived from our published and unpublished preliminary studies demonstrating that: (i) Treatment with ?-TmT significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development in the TRAMP mouse PCa model; (ii) Inhibitory effect of ?-TmT on the formation and growth of LNCaP tumors in the SCID mice; (iii) IHC of re-expression of Nrf2 and anti-oxidative stress/antioxidant genes in ?-TmT-treated TRAMP prostate tumors; (iv) Induction of Nrf2-ARE-mediated gene expression; (v) Inhibition of inflammatory signaling in macrophages; and (vi) Induction of cell death and apoptosis in LNCaP and PC-3 cells. Despite these promising results, however, significant gaps in our understanding of the molecular mechanism(s) of ?-TmT exist in PCa prevention. Studies proposed in this project will not only fill these mechanistic gaps but also determine the in vivo efficacy of ?-TmT for prevention of PCa in 3 animal models. Based on the results of our preliminary studies, we hypothesize that ?-TmT treatment selectively causes Nrf2-dependent anti-oxidative stress response and anti-inflammatory and pro-apoptosis in prostate cancer cells leading to chemoprevention of prostate carcinogenesis. Specific Aims: The specific aims of this project are to: (1) Investigate the chemopreventive efficacy of dietary ?-TmT, ?-T, (-T, and (-T in the TRAMP as well as Nrf2 KO/TRAMP mouse PCa models; (2) Determine the chemopreventive efficacy of dietary ?-TmT, ?-T, (-T, and (-T on the growth and progression of LNCaP orthotopic xenograft tumors in SCID mice; (3) Examine the in vivo cancer preventive markers in the tumor samples generated from Aims 1 and 2; (4) Elucidate the in vitro molecular mechanisms of anti-tumor effects elicited by T in TRAMP C1, C3, LNCaP and PC-3 cell lines. Significance of the Proposed Research: Selenium and Vitamin E Cancer Prevention Trial (SELECT), a clinical trial to determine if one or both of these cancer chemopreventive substances can help prevent PCa when taken as dietary supplements. The recently published results indicated that selenium (200 g/d) and vitamin E (400 IU/d, (-T), taken alone or together for an average of five years, did not prevent PCa. However, this trial used only (-T and did not use other T or its combination. Positive outcome of this proposed study will drive clinical trials of high ?-T vitamin E (?TmT) dietary supplement for its chemopreventive efficacy against human PCa. Defining the mechanism of anticancer effect of ?TmT and to elucidate critical biomarker(s) of ?TmT response would potentially be useful in future clinical trials and optimization of ?TmT-based chemopreventive regimens against human PCa. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) remains the second leading cause of cancer death in men in the US. The long term goal of this application is to develop an effective and safe strategy for prevention of PCa in men using a novel high content of ? mixed tocopherols (?-TmT), particularly in view of the recent failure of the SELECT trial.